Q1：精準醫學概念的涵義與理解
Dr. Yu: Precision Medicine is the term favored byFrancis Collins, MD, PhD, director of the United States National Institutes of Health, to describe the application ofmolecular data to human health. It was selected to distinguish molecular based medicine from the older term“personalized medicine ” which includesnon-molecular aspects such as patient preferences, lifestyles and the existence of other unrelated health problems that may influence the treatment decisions and out⁃comes of patients.
Precision medicine includes all aspects of molecularmedicine including the germ line and somatic genome(genomics), RNA expression (transcriptome), proteins(proteomics) and metabolites (metabolome). Collective lythese are referred to as Panomics.
The actual molecules that are measured are often referred to as biomarkers. Personalized medicine is sometimes referred to as Individualized Medicine.
President Obama highlighted the growing awareness that precision medicine has tremendous potential to impact all human diseases and at all stages of health care delivery, from prevention to detection to treatment.
Q2：精準醫學在腫瘤治療中應用的優勢與差距
Dr. Yu: For germ line mutations, precision medicine helps us identify special populations that are at heightened risk for developing cancer, such as those carrying BRCA mutations. Patients with cancer harbor acquired mutations that are drivers of cancer growth or provide escape fromapoptosis and immune surveillance.
Understanding these mechanisms of cancer biology will identify targets of treatment and guide new small molecules and antibody development. Protein expression and the metabolome will help us understand the function almolecules and provide additional targets for therapy.
Among the challenges to precision medicine is coning down on the drivers of cancer and other diseases and distinguishing those from the background noise of co-existing molecules that are aberrant, but not related to the disease itself. One example is variants of uncertain significance (VUS). These are mutations found with ingenes associated with cancer, but the clinical significance of which has not yet been characterized. It may be that the mutation does not alter the function of the corresponding protein, in which case the genetic aberrancy is benign and classified as a polymorphism.
Another challenge for precision medicine is the many methodologies for identifying biomarkers, each of which has its own strength and limitations. Does one measure the genetic mutation, the gene copy number for amplification, the gene expression levels or the protein? Should onemeasure more than one as we do with HER-2 when protein expression is equivocal? With next generation sequencing, laboratories differ in primers, depth of analysis and which genes are included for testing.
The lack of standards will limit the ability of research to compare results and clinicians to make consistent treatment decisions.
Q3：精準醫學在腫瘤治療中的短期與長期目標
Dr. Yu: The short-term goals of precision medicine should be to show early proof-of-concept by delivering tangible benefits for human health. Targeted therapies of course are already well beyond the proof-of-concept stage of linkage of biomarkers with the development and selection of drugs, the use of monoclonal antibodies as therapeutic agents and checkpoint inhibitors.
However, the unaffordable and unsustainable cost of these new therapies has created an unmanageable financial burden on both society and individuals that threatens to abort the early successes. If patients cannot gain access to the benefits of precision medicine because drugs do not appear on national formularies or are not covered by insurance policies, precision medicine will fail.
Long term challenges include the emergence of drug resistance due to downstream activation of signal transduction pathways or the activation of accessory pathways. We are already seeing that drug resistance cane merge and emerge predictably within a few months of starting a targeted agent.
It is likely that such resistance development mechanisms are predictable and combinations of agents might be rationally designed. Another long-term challengeis understanding why not all patients respond to therapy equally and what the role of epigenetic alterations may be.
